This invention relates to benzazepine derivatives which are selective for dopamine D-1 receptors, to methods of preparing such compounds, to methods of utilizing them as imaging agents, and to novel compounds useful as intermediates in the preparation of such D-1 receptors.
For the treatment of a wide variety of different nervous and mental diseases, it is desirable to be able to monitor the effectiveness of drugs and substances which affect brain chemistry. For instance, in the treatment of schizophrenia or Parkinson's Disease, it is highly desirable to be able to gauge the biochemical effects of drugs administered for blocking the patient's dopamine receptors. If too little of the drug is administered, the desired blockade does not occur, and if too much of the drug is administered, there can be severe side effects.
New and powerful imaging methods which enable one to assess the living brain in vivo and thereby monitor the effectiveness of drugs and substances that affect brain chemistry have recently been developed. Methods such as positron emission tomography (PET) and single photon emission tomography (SPECT) involve the administration to a patient of radioactive tracer substances comprising a ligand that binds to presynaptic or postsynaptic neuroreceptors in the patient's brain. Emissions (primarily gamma rays which are emitted from the positrons or photons emitted from the radioactive tracer) are measured. These emissions are indicative of the number and degree of occupancy of blocking of the neuroreceptors. The number of neuroreceptors and the degree of occupancy or blocking is calculated utilizing a mathematical model, and compared with an intra-person or interperson control, to determine the degree of drug response. Further treatment of the patient with drugs is based upon the comparisons made.
It is generally accepted that there are two subtypes of dopamine receptors, designated as D-1 and D-2 receptors. Recent reports have suggested that these two subtypes of receptors exhibit opposite biochemical effects: D-1 agonists stimulate adenyl cyclase activity, while D-2 agonists inhibit the enzyme activity. It is clear that these receptor subtypes influence each other, and yet they display separate and distinct functions on body physiology and biochemistry. Monitoring of D-1 receptors in a patient is important for assessing the dopaminergic system and ultimately assisting patient management.
The compound R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl5-phenyl-1H-3-benzazepine-7-ol (SCH-23390) is a highly selective central D-1 antagonist. O'Boyle, K.M., Waddington, T.L., Eur. J. Pharmacol., 1985, 115, 291; Seeman, P., Niznik, H.B., Atlas of Science: Pharmacology 161, 1988. The corresponding bromo- and iodo- compounds (SKF-83566 and IBZP, respectively) have also been shown to have a high specificity for central D-1 dopamine receptors. Friedman, A.M., Dejesus, O.T., Woolverton, W.L., et al., Eur. J. Pharmacol., 1985, 108, 327; Manik, C.P., Molinoff, P.B., McGonigle, P., J. Neurochemistry, Vol. 51, No. 2, p. 391, 1988; Kung, H.F., Billings, J., Guo, Y.-Z., Blau, M., Ackerhalt, R.A., Intl. J. Nucl. Med. Biol., 1988, 15, 187; McQuade, R.D., Chipkin, R., Amlaiky, N. et al., Life Sciences, Vol. 43, pp. 1151-1160 (1988). The in vitro affinity constants for these compounds in the rat striatum tissue preparation are set forth in Table 1.
TABLE 1 ______________________________________ Chemical Structures and In Vitro Binding Constants of Benzazepines Compound X Kd (nM) ______________________________________ ##STR1## SKF-83692 SCH-23390 SKF-83566 IBZP H Cl Br I 197 0.36 2.32 0.7 ______________________________________
The bromo compound SKF-83566 labeled with .sup.86 Br, a positron emitting radionuclide, has been used for PET (positron emission tomography) imaging in a rhesus monkey, which showed the highest concentration in the basal ganglia, with more selectivity in the posterior aspect of the caudate nucleus, the region with high D-1 receptor density. Friedman, A.M., Dejesus, O.T., Woolverton, W.L., supra. Several recent reports have indicated that in conjunction with PET, [.sup.11 C]SCH-23390 showed the highest concentration in the basal ganglia area of the human brain. Farde, L., Halldin, C., Stone-Elander, S., et al., Psychopharmacol., 1987, 92, 278; McQuade, R.D., Ford, D., Duffy, R.A., Chipkin, R.D., Iorio, L.C. and Barnett, A., Life Sciences, Vol. 43, pp. 1861-1869 (1988).
The potential of a radioiodinated benzazepine derivative, [.sup.125 I]BZP as a specific CNS D-1 dopamine receptor imaging agent for SPECT has been reported. Kung, H.F., Billings, J., Guo, Y.-Z., Blau, M., Ackerhalt, R.A., Id. The agent exhibited good localization in rat brains after an intravenous injection, with an uptake of 2.7, 1.2, 0.8 and 0.26 %dose/organ at 2, 15, 30 and 60 minutes post injection, respectively. The regional distribution of [.sup.125 I]BZP in rat brain, as measured by in vivo autoradiography, displayed a high uptake in the caudate putamen, accumbens nucleus and substantia nigra, regions known to have a high concentration of D-1 dopamine receptors. The uptake ratio of striatum/cerebellum increased with time. At thirty seconds and two hours after injection, the ratios were 1.1 and 5.3, respectively. The specific uptake regions (as measured by in vivo autoradiography), rich in D-1 dopamine receptors, can be blocked by pretreatment with SCH-23390, a selective D-1 dopamine receptor antagonist.
IBZP suffers two major disadvantages as a potential imaging agent. The first disadvantage is the poor in vivo and in vitro stability of the compound based on observations of the in vivo biodistribution study of [.sup.125 I] IBZP in rats. The thyroid uptake is high at later time points, which strongly suggests the availability of free iodide in the blood circulation due to in vivo deiodination. Deiodination may take place because the radioactive iodine is at an activated position, ortho to the hydroxyl group on the benzene ring. The second drawback of [.sup.125 I] IBZP is its short retention time in the brain. In a normal SPECT study of the brain, it takes about thirty to sixty minutes for the data acquisition. It is necessary to use an agent exhibiting a prolonged retention time in the target region (in this case, basal ganglia) for SPECT imaging studies.
Although the compound SCH-23390 is a highly selective D 1 antagonist, its use as an imaging agent is diminished by the absence of a diagnostically suitable radioisotope such as .sup.123 I.
There is, therefore, a need for improved CNS D-1 dopamine receptor imaging agents which overcome the disadvantages of the various imaging agents known in the art.